1. Field of the Invention
This invention relates to the use of enkephalinase or endorphinase inhibitors, and, optionally, dopamine precursors, serotonin precursors and/or GABA precursors, in the treatment of cocaine addiction.
2. Information Disclosure Statement
Cocaine is a naturally occurring stimulant derived from the leaves of the coca plant, Erythroylon coca. In 1864, cocaine was isolated from the coca leaves.
Coca leaves contain only about one-half of one percent pure cocaine alkaloid. When chewed, only relatively modest amounts of cocaine are liberated, and gastrointestinal absorption is slow. Certainly, this explains why the practice of chewing coca leaves has never been a public health problem in Latin America. The situation changes sharply with the abuse of the alkaloid itself.
The cocaine user experiences three stages of drug effects. The first, acute intoxication ("binge"), is euphoric, marked by decreased anxiety, enhanced self-confidence and sexual appetite, and may be marred by sexual indiscretions, irresponsible spending, and accidents attributable to reckless behavior. The second stage, the ("crash"), replaces euphoria by anxiety, fatigue, irritability and depression. Some users have committed suicide during this period. Finally, the third stage, "anhedonia," is a time of limited ability to derive pleasure from normal activities and of craving for the euphoric effects of cocaine. See Gawin and Kleber, Medical Management of Cocaine Withdrawal, 6-8 (APT Foundation).
In the past, physicians tended to treat primarily the acute symptoms of cocaine abuse, prescribing drugs such as propranolol to treat erratic heart rhythms, diazepam to control convulsions and chlorpromazine to relieve psychosis (paranoia). However, these treatment approaches do not relieve the patient's craving for cocaine.
A number of drugs have been suggested for use in weaning cocaine users from their dependency. Antidepressants, such as lithium and desipramine, were studied by Tennant and Rawson, in PROBI,EMS OF DRUG DEPENDENCE 1982, 351-55 (NIDA Res. Monogr. Ser. 43, 1983); Gawin, Psychosomatics, 27: 24-29 (1986); Gawin and Kleber, Arch. Gen. Psychiatry, 41: 903-9 (1984); Kleber and Gawin, J. Clin. Psychiatry 45 (12, Sec. 2): 18-23 (1984).
Certain therapeutic agents are favored by the "dopamine depletion hypothesis." It is well established that cocaine blocks dopamine re-uptake, acutely increasing synaptic dopamine concen&:rations. However, in the presence of cocaine, synaptic dopamine is metabolized as 3-methoxytyramine and excreted. The synaptic loss of dopamine places demands on the body for increased dopamine synthesis, as evidenced by the increase in tyrosine hydroxylase activity after cocaine administration. When the precursor supplies are exhausted, a dopamine deficiency develops. See Dackis and Gold, Neurosc:i. Biobehav. Rev., 9:469-77 (1985); Gold and Dackis, Clin. Therapeutics, 7:6-21 (1984). This hypothesis led to the testing of bromocriptine, a dopamine receptor agonist. Dackis, et al., Int. J. Psychiat. Med., 15: 125-135 (1985); Tennant and Sagherian, Arch. Intern. Med., 147:109 (1987). A second approach was the administration of amantadine, a dopamine releaser. Another approach, also based on this hypothesis, was to provide a precursor for dopamine, such as L-dopa, See Rosen et al., Am. J. Psychiat., 143:1493 (Nov. 1986), or L-tyrosine, Gold, et al., Soc. Neurosci. Absts., 9:157 (1983); Rosecan, Abstract, VII World Congress of Psychiatry, Vienna, Austria (1983);
Agonists are not preferred therapeutic agents. A given agonist may act on several receptors, or similar receptors on different cells, not just on the particular receptor or cell one desires to stimulate. As tolerance to a drug develops (through changes in the number of receptors and their affinity for the drug), tolerance to the agonist may likewise develop. A particular problem with bromocryptine is that it may itself create a drug dependency. It is known that bromocriptine is self-administered by rhesus monkeys. Woolverton, et al., J. Pharm. Exptl. Therap. 230(3): 678-683 (1984).
Releasers are effective only if they have something to release. They will not cure a state of dopamine depletion. Indeed, we would be concerned that dopamine releasers, used alone, would exacerbate the chronic depletion of dopamine.
Precursors use a naturally regulated pathway. The precursor is converted to the neurotransmitter only when needed, and then the body distributes the product on the basis of need. As dopamine is synthesized from precursors such as L-tyrosine, dopamine reserves are rebuilt, thus overcoming the dopamine depletion problem.
Verebey and Gold, in PSYCHOPHARMACOLOGY: IMPACT ON CLINICAL PSYCHIATRY 219-41 (Morgan, ed., 1985) (1985), describe a regimen for the treatment of cocaine addiction that contemplates administration of L-tyrosine, L-tryptophan, thiamine, riboflavin, niacin, pantothenic acid, pyridoxamine, ascorbic acid, folic acid and cyanocobalamin. Their composition does not include any enkephalinase or endorphinase inhibitor or any enkephalin or endorphin releaser. Nor does it include any GABA precursor.
D-phenylalanine is an inhibitor of enzymes involved in the metabolism of endorphins and enkephalins. Ehrenpreis, Subs Alc Act/Mis, 3: 231-239 (1982). It has anti-alcohol craving activity, see copending U.S. application Ser. No. 06/757,733 and counterpart PCT Publ WO 86/01495, and has been studied as a potential anti-depressive, Heller, U.S. Pat. No. 4,355,044; Heller in Modern Pharmacology 397 (Mosnaim and Wolf, 1978); and analgesic agent, see Ehrenpreis, U.S. Pat No. 4,439,452. There have been no reports of its use in the treatment of cocaine addiction.
L-Tyrosine is a precursor of dopamine see Wurtman, et al., Science, 185: 183-4 (1974); Gibson and Wurtman, Biochem. Pharmacol., 26: 1137-42 (1977). L-tyrosine has been suggested as an anti-depressant. See Gelenberg et al., Am J Psychiat 137:622 (1980).
L-tryptophan is a precursor of serotonin. See Fernstrom and Wurtman, Science, 174: 1023-25 (I971), Eccleston, et al., J. Neurol. Neurosurg. psychiatry, 33: 269-72 (1970). This amino acid has been used to treat food craving. Wurtman, et al., lnt., J. Eating Disord. 1: 2-15 (1981); but its effect on craving is uncertain. See Leathwood and pollet, J. Psychiatr. Res., 17: 147-54 (1983). lt has also received mixed reviews as an anti-depressant. Finally, L-tryptophan has been used to enhance sleep and to reduce pain. See Young, in Nutrition and the Brain, Vol. 7, 49-86 (Wurtman and Wurtman, 1986); Lieberman, et al., J. Psychiatric Res., 17: 135-145 (1983).
L-glutamine is a precursor of the neurotransmitter gamma aminobutyric acid (GABA). L-glutamine has been used to reduce voluntary alcohol consumption in rats. Rodgers, et al., J. Biol. Chem. 214: 503-506 (1955); Ostrovsky, Substance Alcohol Actions/Misuse 5: 247-253 (1984).
No admission is made that any of the foregoing references are prior art, or as to the pertinency of any reference.